Hippocampal neurogenesis occurs throughout life and the balance of neuronal loss and birth is essential in generating the plasticity necessary for new memory formation. The generation of new neurons within the hippocampus is mediated by proliferating neural stem/progenitor cells that are exquisitely sensitive to local signaling. Stem cells represent the most immature cell necessary for neurogenesis. These cells gives rise to more restricted precursors or progenitor cells and ultimately these progenitors differentiate into new functional neurons. These cells produce neurons in response to signals received from surrounding cells as well as humoral signals from circulating hormones, cytokines, and growth factors. Gross alterations in local microenvironments may allow ectopic neurogenesis to occur, or even block essential neurogenesis, leading to deficits in neurogenesis-dependent functions, such as learning and memory. Within this relatively new field of study, a paradigm of neural stem/progenitor cell dysregulation is emerging. Stress and the accompanying changes in stress hormones orchestrated by the hypothalamic-pituitary-adrenal (HPA) axis suppress hippocampal neurogenesis and lead to deficits in learning and memory. Glucocorticoids have played a central role in modeling this process but other factors also change with alterations in the HPA axis. Notable among these is the apparent link between pro-inflammatory cytokines and glucocorticoids. Inflammation and subsequent elevations of interleukin-1β (IL-1β) lead to the robust elevation of glucocorticoids via the HPA axis. Inflammation is also accompanied by the central production of pro-inflammatory cytokines. Among these are interleukin-6 and tumor necrosis factor-α (TNFα) which are found to be inhibitory to neurogenesis.
It is well-known that radiation is damaging to cells. Initial deposition of energy in irradiated cells occurs in the form of ionized and excited atoms or molecules distributed at random throughout the cells. It is the ionizations that cause most of the chemical changes in the vicinity of the event, by producing a positively charged or “ionized” molecule. These molecules are highly unstable and rapidly undergo chemical change to produce free radicals, atoms, or molecules containing unpaired electrons. These free radicals are extremely reactive and can lead to permanent damage of the affected molecule. As an immediate consequence of radiation damage, cells can undergo apoptosis, dying in interphase within a few hours of irradiation. Radiation damage can be acute, or can be manifested long after the initial event.
Cranial radiation therapy, a crucial treatment for brain tumors and other cancers, causes a progressive and debilitating decline in learning and memory. Cranial irradiation ablates hippocampal neurogenesis by damaging the neurogenic microenvironment. Endogenous neurogenesis is inhibited after irradiation despite the presence of neural precursor cells that retain the ability to make neurons, and neurogenesis is likewise inhibited for non-irradiated precursor cells transplanted to the irradiated hippocampus.
The investigation and development of methods to prevent this impairment in neurogenesis is of great clinical interest.
Publications
The appearance of activated microglia in the brain is a common indicator of the inflammatory process and neuroinflammation and accompanying microglial pathology, which are associated with many diseases of cognition in which memory loss features prominently, such as Alzheimer's Disease, Lewy Body Dementia, and AIDS Dementia Complex. Clinical treatment with indomethacin and other NSAIDs has been demonstrated to ameliorate the risk and progression of memory loss (Rogers et al. (1993) Neurology 43:1609-1611; (2001) N. Engl. J. Med. 345:1515-1521).